(1) Treatment of patients with hepatitis B-associated liver failure
In China, HBV infection is the main cause of liver failure. HBV-related liver failure can be further divided into acute liver failure, subacute liver failure, slow-plus-acute liver failure and chronic liver failure. In principle, early diagnosis and treatment, as well as timely disease assessment and intensive care treatment are emphasized. Artificial liver support therapy can be performed according to the indications if available, and liver transplantation prep is performed depending on the progress of the disease. Nucleoside (acid) analogs (NAs) can be safely applied in the treatment of patients with HBV-related liver failure and can improve the prognosis of patients, prolong the survival of liver failure and potentially avoid liver transplantation.
NAs used in patients with HBV-related acute and subacute liver failure may improve their survival and reduce the incidence of complications associated with liver failure. Early antiviral therapy with NAs should be considered for patients with HBsAg-positive or HBVDNA-positive acute and subacute liver failure. Antiviral treatment with NAs in patients with chronic plus acute and chronic liver failure can also improve the disease, increase survival and reduce the risk of hepatitis B recurrence after liver transplantation. For patients with early and mid-stage HBV-related chronic plus acute liver failure, antiviral therapy can be considered if HBV DNA is positive; patients with advanced chronic plus acute liver failure and chronic liver failure, who often require liver transplantation, should be treated with antiviral therapy as long as HBsAg or HBV DNA is positive.
For all types of patients with liver failure it is recommended to apply NAs with rapid viral inhibition such as entecavir (ETV), tenofovir (TDF), lamivudine (LAM) or telbivudine (LdT), and long-term application should be monitored for the occurrence of drug resistance, and it is recommended to give preference to highly effective, low resistance antiviral drugs (ETV and TDF). If a drug with a high risk of resistance (e.g. LAM) is used, HBV DNA should be closely monitored and a non-cross-resistant antiviral drug [e.g. adefovir (ADV)] should be combined early if a poor response or viral rebound is detected.
If HBsAg and HBV DNA are below the lower limit of detection during antiviral therapy, the residual HBV in the body cannot be completely ruled out, so antiviral therapy should be continued until HBsAg serological conversion occurs. viral mutation during NAs therapy can lead to aggravation of the disease, and should be combined with non-cross-resistant NAs for treatment as early as possible.
(2) Treatment of hepatitis B-associated liver transplant patients
Liver transplantation has become an effective treatment option for patients with liver failure and early stage HCC. However, recurrence of HBV infection after transplantation has been an important issue affecting survival after transplantation. All HBsAg-positive patients presenting with HBV-associated end-stage liver disease or HCC awaiting liver transplantation should be treated with NAs to achieve the lowest possible serum HBV DNA level prior to transplantation.
Combination therapy with NAs/high-valent hepatitis B immunoglobulin (HBIG) is effective in preventing reinfection of the transplanted liver and can reduce the risk of infection in the transplanted liver to less than 10%. Our guidelines recommend that patients with HBV-related liver disease who are proposed to undergo liver transplantation should preferably start taking NAs 1-3 months before liver transplantation; give HBIG during the intraoperative liver-free period; and use NAs and low-dose HBIG (800 IU daily for the first week and 800 IU weekly to 800 IU monthly application thereafter) for a long time after surgery.
In addition, a single long-term treatment with NAs may be considered for patients with a low risk of relapse (HBV DNA negative before liver transplantation and no relapse 2 years after transplantation). Although LAM has a better safety profile and is well tolerated by patients both before and after transplantation, long-term LAM monotherapy may lead to the emergence of LAM resistance, which may cause late post-transplant HBV relapse, so patients with poor efficacy should be treated early with a combination of another NAs without cross-resistance.
Recently, it has been shown that ETV and TDF monotherapy can safely and effectively prevent HBV relapse. Therefore, ETV or LAM plus ADV combination therapy can be used as a long-term drug option to prevent HBV reinfection. Patients who have not been infected with HBV who receive livers from anti-HBc-positive donors are at great risk of HBV infection and should therefore also receive long-term NAs therapy or HBIG prophylaxis.
(3) Patients treated with immunosuppressive or cytotoxic drugs
20-50% of HBV carriers who receive immunosuppressive or cytotoxic drugs will experience reactivation of HBV replication, as evidenced by elevated serum HBV DNA and ALT levels. Some of these patients may develop jaundice, and in severe cases, liver failure or even death. HBV reactivation is more likely to occur if glucocorticoids or rituximab are included in the treatment regimen. In addition, HBV reactivation has been reported in HBsAg-positive patients with hepatocellular carcinoma receiving intra-arterial infusion chemotherapy and in patients with rheumatoid arthritis or inflammatory bowel disease receiving other immunosuppressive agents such as anti-tumor necrosis factor drugs like infliximab. prophylactic treatment with NAs reduces the incidence of HBV reactivation, the extent of liver inflammatory necrosis, and the rate of death due to HBV reactivation.
For patients at high risk of HBV infection, HBsAg and anti-HBc should be monitored before starting chemotherapy or immunosuppressive therapy. hepatitis B vaccination is recommended for patients with negative HBV virological markers. For HBV carriers (regardless of their baseline serum HBV DNA levels), prophylactic treatment with NAs should be administered 2-4 weeks prior to treatment with immunosuppressive or cytotoxic drugs.
After cessation of immunosuppressive and cytotoxic drug therapy, drug and regimen selection should be based on the patient’s baseline HBV DNA load and the expected course of immunosuppressive and cytotoxic drugs: for patients with baseline HBV DNA < 2000 > 2000 IU/ml), therapy should be continued until the same treatment endpoint is reached as in immunocompetent chronic hepatitis B patients. For patients with a shorter expected course (≤12 months) and baseline HBV DNA below the lower limit of detection, drugs with rapid HBV DNA inhibition, such as ETV, LAM or LdT, can be used. for longer expected courses (>12 months), drugs with a lower incidence of resistance, such as ETV or TDF, are preferred.
Patients who are HBsAg negative and anti-HBc positive are also at risk of HBV reactivation, and there is no consensus on the need for prophylactic treatment in this population. Considering that patients with hematologic malignancies treated with rituximab and/or hormonal combination therapy who are HBsAg negative, anti-mono-HBs negative, and anti-HBc positive by hepatitis B markers are still at high risk of HBV replication reactivation, it is recommended that they all need to receive NAs therapy. Prophylactic NAs therapy is also recommended for anti-HBc-positive patients undergoing bone marrow or stem cell transplantation. All HBsAg-negative, anti-HBc-positive patients should be closely monitored for HBV virological markers and HBV DNA load during treatment.
(4) Patients with combined autoimmune thyroid disease
HBV infection itself is not clearly correlated with abnormal thyroid function. When antiviral therapy is required in patients with chronic hepatitis B with autoimmune thyroid disease, treatment with NAs generally does not affect the course of thyroid disease. If IFN-α is used as an antiviral treatment for chronic hepatitis B, its immunomodulatory activity and direct thyrotoxic effects need to be considered, and some patients with pre-existing autoimmune thyroid disease may experience worsening or new thyroid disease.
In prospective studies of chronic hepatitis B patients treated with IFN-α antiviral therapy, 3.6-3.9% of patients presented with clinical and/or biochemical thyroid function abnormalities prior to treatment, and 10.2%-12.3% of patients were positive for thyroid autoantibodies (anti-thyroid peroxidase antibody TPOAb, anti-thyroglobulin antibody TgAb) and had normal thyroid function. Asymptomatic increases in titers of pre-existing thyroid autoantibodies may occur during antiviral therapy.
Less than 10% of patients who were negative for white body antibodies prior to treatment had newly elevated thyroid white body antibody levels during treatment. Only a small number of patients (2-4.2%) progress from normal thyroid function to abnormal thyroid function during treatment. High pre-treatment titers of thyroid autoantibodies (IPOAb titers >18 IU/ml) correlate with new thyroid function abnormalities during treatment. most thyroid function abnormalities are reversible after the end of IFN-α treatment.
Therefore, antiviral therapy with IFN-α should not be administered to patients with uncontrolled thyroid dysfunction, and if antiviral therapy is necessary, NAs are preferred. patients with previous thyroid dysfunction or high pre-treatment thyroid autoantibody titers (TPOAb titers >18 IU/ml) should be monitored for thyroid function during antiviral therapy with IFN-α, and patients with thyroid dysfunction during treatment should be discontinued if necessary. Patients with abnormal thyroid function during treatment should stop IFN-α therapy and switch to NAs if necessary.
(5) Patients with combined renal disease
Patients with chronic hepatitis B combined with renal disease should consider two conditions: HBV-related renal damage, mainly HBV-associated glomerulonephritis (HBV-AG); and other renal diseases, such as hypertension or diabetic nephropathy, mainly in patients with chronic renal insufficiency.
Antiviral therapy is the key to treat HBV-AG. Several clinical studies have reported that LAM treatment for HBV-AG results in significant remission of renal disease with HBV DNA suppression and HBeAg clearance. Some clinical trials have shown that NAs can cause an increase in blood creatinine levels in some patients, therefore, ADV or TDF should be carefully selected for the treatment of HBV-AG patients; LdT and ETV can also be used for the treatment of HBV-AG patients. Antiviral therapy. There is less definitive evidence for the use of regular IFN or PegIFN for the treatment of HBV-AG.
The proportion of HBV-infected patients with end-stage renal disease is high in China. HBV screening is recommended for patients with kidney disease. Although such patients may not respond well to hepatitis B vaccine, patients with negative HBV virological markers should still receive vaccination. Patients with chronic hepatitis B with renal insufficiency may be treated with NAs or IFN. All medications, especially NAs, require dose adjustment and caution based on the patient’s renal function. Avoid drugs with potential renal toxicity. Patients’ renal function should be monitored during antiviral therapy, and any sudden deterioration in renal function may necessitate a change in therapy or further adjustment of drug dose. Aggressive control of the patient’s hypertension and diabetes mellitus is also required.
IFN is contraindicated in renal transplant recipients because of the risk of rejection. Each HBsAg-positive kidney transplant recipient receiving immunosuppression requires anti-HBV therapy with one of the NAs. The need for antiviral prophylaxis also needs to be evaluated continuously and frequently in all HBV-positive renal transplant recipients. It is important to note that, given the potential nephrotoxicity of ADV, antiviral therapy with NAs with low resistance genetic barriers such as LAM or LdT should be used with caution especially in renal insufficiency and renal transplant recipients, who may not be able to routinely add ADV as salvage therapy in the event of poor virologic response or even drug resistance.
(6) Treatment of pregnant patients
Mother-to-child transmission of HBV is the main route of transmission of HBV infection in China, and antiviral therapy for pregnant patients is particularly important.
Before starting anti-HBV therapy in women of childbearing age, patients with fertility requirements should be fully informed of the safety of antiviral drugs in pregnancy. iFN is contraindicated in pregnant patients. the FDA classifies LdT and TDF as class B drugs in pregnancy (no teratogenic risk in animal studies, but uncertain in humans) and LAM, ADV and ETV as class C drugs in pregnancy (teratogenic risk in animal studies, but uncertain in humans). Extensive data from antiretroviral drug pregnancy registries suggest the safety of applying TDF plus/ or LAM or emtricitabine to HIV-positive pregnant patients. TDF should be preferred among these agents because of its high genetic barrier to resistance and the well-documented safety profile in HBV-positive pregnant patients.
Due to the unique nature of pregnancy, treatment needs to be tailored to the different pregnancy states.
Antiviral therapy for patients with chronic hepatitis B in pregnancy requires consideration of the safety of antiviral drugs in pregnancy. Patients with fertility requirements should try to have effective antiviral therapy before pregnancy with a view to completing antiviral therapy in the first 6 months of pregnancy.
For women of childbearing age who are planning a recent pregnancy and do not have progressive liver fibrosis, antiviral therapy can be administered after delivery. For patients planning a recent pregnancy with more severe liver disease, the application of antiviral therapy may be considered after full consultation and signing of an informed consent form. Due to the limited course of IFN, interferon therapy may be considered. However, it is important to note that reliable contraception must be used during IFN treatment. If IFN therapy fails, NAs therapy is initiated and antiviral therapy is maintained during pregnancy. For pregnant patients, TDF and LdT are the preferred treatment options.
Patients who have an unplanned pregnancy while on ART need to be re-evaluated for treatment indications. The indication for treatment remains the same for pregnant patients with a first diagnosis of chronic hepatitis B during pregnancy. Patients who develop progressive fibrosis or cirrhosis must continue treatment and then require reconsideration of therapeutic agents; IFN has pregnancy toxicity and patients who have an unplanned pregnancy during antiviral therapy with IFN need to terminate the pregnancy.
Patients with unintended pregnancies during antiviral therapy with NAs may continue treatment with adequate information about the risks, weighing the pros and cons, and with the patient signing an informed consent form, but need to switch from gestational class C NAs, such as ADV and ETV, to class B NAs class drugs. Among gestational class B NAs, TDF therapy is preferred because of its effective antiviral properties and high resistance genetic barrier, as well as ample data demonstrating its safety in pregnant patients.
Mother-to-child transmission of HBV often occurs at delivery, and serum HBV DNA load in pregnant patients is one of the key factors in mother-to-child transmission, and effective antiviral therapy can significantly reduce the incidence of mother-to-child transmission of HBV. In general, hepatitis B immunoglobulin (HBIG) passive immunization and HBV vaccine active immunization are used to prevent mother-to-child transmission of HBV. However, fetuses of mothers with hypervirulence (serum HBV DNA >107 IU/ml) using this regimen are still at risk for HBV infection.
Pregnant patients with high HBV DNA loads may be treated with NAs to reduce viral load and thereby increase the preventive effect of HBIG and hepatitis B vaccine. If a pregnant patient does not receive any anti-HBV therapy, or if anti-HBV therapy is interrupted during pregnancy, or if she delivers prematurely for any reason, the patient must be monitored closely because of the risk of a hepatitis flare-up, especially after delivery.
The safety of NAs treatment during lactation is unclear. HBsAg can be measured in breast milk, yet HBsAg-positive mothers are not prohibited from breastfeeding. TDF concentrations in breast milk have been reported, but because the bioavailability of oral dosing is very limited, the infant is actually exposed to very low concentrations of the drug.
For male patients on IFN antiviral therapy, pregnancy should not be considered for their wives until 6 months after discontinuation of the drug. For male patients on NAs antiviral therapy, there is no evidence that NAs treatment has adverse effects on sperm and the fetus, and fertility can be considered with adequate communication with the patient.
(7) Treatment of patients with co-infection with HCV or HIV
Chronic hepatitis B patients can be co-infected with HCV, and HBV/HCV co-infection can accelerate the progression of liver disease and increase the incidence of cirrhosis and hepatocellular carcinoma. HBV and HCV can replicate in the same hepatocyte without interfering with each other. HCV infection inhibits HBV infection and most patients have low HBV DNA levels.
It has been shown that the rate of sustained virologic response to HCV is comparable in co-infected patients to that of HCV monoinfected patients. During HCV treatment or when HCV is cleared, patients are at risk of HBV reactivation as the suppressive effect of HCV on HBV infection is lifted. Therefore, HBV DNA levels must be monitored during the course of treatment. Once HBV reactivation occurs, treatment with NAs must be received.
Our expert consensus on antiviral therapy for special patients with chronic hepatitis B proposes a reference protocol for antiviral therapy in patients with HBV/HCV co-infection. The treatment of co-infected patients should be integrated with the patient’s HBV DNA load, HCV RNA load and ALT status to adopt different treatment regimens.
HIV co-infection increases HBV DNA load, decreases white blood HBeAg seroconversion rate, aggravates liver lesions and increases the mortality rate associated with liver disease. The indications for anti-HBV treatment in co-infected patients are the same as for HIV-negative patients, depending on the patient’s HBV DNA level, serum ALT level and histological changes, and need to be combined with the patient’s highly active antiretroviral therapy (HAART) treatment. Treatment should be administered to patients who meet the criteria for treatment of chronic hepatitis B. Liver tissue biopsy should be considered in patients with transient or mild ALT elevations [(1-2 x UNL].
For patients who are not on HAART or do not require HAART in the near future, anti-HBV therapy should be administered with a regimen without anti-HIV active agents, such as PegIFN-α or ADV. LAM, TDF and ETV are not recommended for such patients due to the risk of inducing HIV resistance with monotherapy.
For patients who require concurrent anti-HBV and HIV therapy, a regimen that inhibits both viruses should be selected: LAM plus TDF or emtricitabine plus TDF is preferred. for patients already receiving effective HAART therapy, PegIFN-α or ADV may be selected if no anti-HBV active agent is available in the regimen. For patients who develop LAM resistance, TDF therapy should be added.
When a change in HAART regimen is required, existing effective anti-HBV drugs should not be discontinued without an alternative effective drug available, unless the patient has achieved HBeAg serologic conversion and has completed a sufficient period of consolidation therapy.